Substituted 2-pyridylmethylthio- and sulfinyl-benzimidazoles as gastric antisecretory agents

ABSTRACT

The present invention provides novel substituted 2-pyridylmethylthio- and sulfinyl-benzimidazoles with gastric acid inhibiting effects.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of copending application Ser.No. 558,087, filed Dec. 5, 1983, now abandoned.

BACKGROUND OF THE INVENTION

The present invention involves novel compositions of matter. Moreparticularly, the present invention involves novel substituted2-pyridylmethyl-thio and -sulfinyl benzimidazoles which are useful asgastric antisecretory and cytoprotective agents.

Gastrointestinal inflammatory diseases are characterized byinflammation, specifically by the presence of edema, characteristicinflammatory cells (i.e., leukocytes, histiocytes, and macrophages),and, in some cases, necrosis and ulceration of the surface epithelium.These inflammatory diseases are known to be caused by a wide variety ofagents present in the gastrointestinal tract which are known to attackthe surfaces thereof, producing the inflammatory disease response. Suchagents include micro-organisms (viruses and fungii), bacterial toxins,certain pharmaceutical agents (antibiotics and antiinflammatorysteroids), and chemical agents (bile salts, toxic household chemicals).Gastric acid itself is also capable of attacking the stomach lining andproducing an inflammatory state.

One means of preventing or treating certain gastrointestinal diseases,specifically gastric diseases, is by the inhibition of gastric acidsecretion. In situations where the integrity of the gastric mucosalbarrier is compromised, gastric acid secretion can result in erosion ofthe epithelial cells with consequent inflammation and ulceration.Inhibition of such untoward gastric acid-induced effects can be achievedby the administration of a pharmacological agent effective to inhibitgastric secretion.

One class of such agents effective to inhibit gastric acid secretion arethe gastric antisecretory prostaglandins. These substances are known tobe effective in the treatment and care of gastric and duodenal ulcers asa result of the inhibition of gastric secretion. See, e.g., U.S. Pat.No. 3,903,297 (Robert, "Method of Treatment and Prophylaxis of GastricHypersecretion and Gastric Duodenal Ulcers Using ProstaglandinAnalogs"), and Robert, "Antisecretory Property of Prostaglandins,"Prostaglandin Symposium of the Worcester Foundation for ExperimentalBiology 16-17 Oct., 1967, Interscience, New York, page 47 (1968).Another important class of antisecretory agents are the histamine H₂receptor antagonists, including metiamide and most importantlycimetidine,N-cyano-N'-methyl-N"[2-[[(5-methyl-1H-imidazole-4-yl)methyl]thio]ethyl]guanidine.See, the Merck Index, 9th Edition, Appendix, page App-1 (1976), andPhysician's Desk Reference, 36th Edition, 1812-1814 (1982).

Another means of treating such gastrointestinal diseases is throughcytoprotection. Certain pharmacological agents have heretofore beenknown to be useful in exerting a cytoprotective effect on thegastrointestinal tract. This cytoprotective effect is manifest in theability of such compounds to treat or prevent non-traumatically-induced,non-neoplastic inflammatory disease of the gastrointestinal tract.References describing such cytoprotective effects of prostaglandins areU.S. Pat. No. 4,083,998 (Robert, "Treatment of Inflammatory Diseases ofthe Mammalian Large Intestine with Cytoprotective Prostaglandins"),issued Apr. 11, 1978; U.S. Pat. No. 4,081,553 (Robert, "CytoprotectiveProstaglandins for Use in Intestinal Diseases"), issued Mar. 28, 1978;and U.S. Pat. No. 4,097,603 (Robert, "Gastric Cytoprotection withNon-Antisecretory Doses of Prostaglandins"), issued June 27, 1978.Gastric cytoprotection is a distinct pharmacological property which isunrelated to gastric antisecretory effects. See, e.g., Robert, U.S. Pat.No. 4,097,603, "Gastric Cyptoprotection with Non-Antisecretory Doses ofProstaglandins," Robert, "Cytoprotection by Prostaglandins,"Gastroenterology 77:761-767 (1979); Robert, "Current History ofCytoprotection," Prostaglandins 21 (supp):89 (1981), and Robert, et al.,"Cytoprotection by Prostaglandins in Rats," Gastroenterology, 77:433-443(1979). Thus, compounds which are gastric anti-secretory agents may notbe cytoprotective agents and vice-versa.

PRIOR ART

U.S. Pat. No. 4,045,563 discloses certain substituted2-[pyridylalkylenesulfinyl]-benzimidazoles having gastric acid secretioninhibiting effects. U.S. Pat. No. 4,255,431 discloses certain2-(2-benzimidazolyl)-pyridines which are useful in inhibiting gastricsecretion. U.S. Pat. No. 4,337,257, discloses some additional2-(2-benzimidazolyl)-pyridines which are useful in inhibiting gastricsecretion. Finally, U.S. Pat. No. 4,359,465 discloses the cytoprotectiveuse of certain heterocyclyalkylsulfinylbenzimidazoles.

SUMMARY OF THE INVENTION

The present invention particularly provides: a compound of the FormulaI,

wherein X is

(a) ═S, or

(b) ═SO;

wherein R₁ is

(a) hydrogen,

(b) methyl,

(c) methoxy, or

(d) trifluoromethyl;

wherein R₂ is

(a) --SR₅,

(b) --OR₅,

(c) --N(R₄)₂

(d) 1-piperidinyl,

(e) 4-morpholinyl,

(f) 4-methyl-piperazin-1-yl, or

(g) 1-pyrrolidinyl;

wherein R₅ is

(a) (C₁ -C₄)alkyl,

(b) (C₁ -C₄)alkenyl,

(c) PhX,

(d) --CH₂ --PhX, or

(e) (C₄ -C₁₀)cycloalkyl;

wherein (PhX) is phenyl substituted by zero to 3 of the following:

(a) (C₁ -C₄)alkyl,

(b) chloro,

(c) fluoro,

(d) bromo,

(e) nitro,

(f) trifluoromethyl; or

(g) OR₃ ;

wherein R₃ and R₄ are the same or different and are

(a) hydrogen, or

(b) (C₁ -C₄)alkyl;

with the proviso that when R₂ is --OR₅, and R₅ is (C₁ -C₄)alkyl, R₃ isother than hydrogen or methyl.

The carbon atom content of various hydrocarbon-containing moieties isindicated by a prefix designating the minimum and maximum number ofcarbon atoms in the moiety, i.e., the prefix (C_(i) -C_(j)) indicates amoiety of the integer "i" to the integer "j" carbon atoms, inclusive.Thus (C₁ -C₄) alkyl refers to alkyl of one to 4 carbon atoms, inclusive,or methyl, ethyl, propyl, butyl, and isomeric forms thereof.

Examples of (C₃ -C₁₀)cycloalkyl which include alkyl-substitutedcycloalkyl, are cyclopropyl, 2-methylcyclopropyl,2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl,cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl,2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl,2-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl,4-tertbutylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl,cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl.

Examples of (C₂ -C₄)alkenyl include 1-propenyl, 3-butenyl and isomericforms thereof.

Examples of PHX include phenyl, (o-, m-, p-)tolyl, (o-, m-,p-)ethylphenyl, 2-ethyl-tolyl, 4-ethyl-o-tolyl, 5-ethyl-m-tolyl, (o-,m-, or p-)propylphenyl, 2-propyl-(o-, m-, or p-)tolyl,4-isopropyl-2,6-xylyl, 3-propyl-4-ethylphenyl, (2,3,4-, 2,3,6-, or2,4,5-)trimethylphenyl, (o-, m-, or p-)fluorophenyl, (o-, m-, orp-trifluoromethyl)phenyl, 4-fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-,or 3,5-)difluorophenyl, (o-, m-, or p-)chlorophenyl, 2-chloro-p-tolyl,(3-, 4-, 5- or 6-)chloro-o-tolyl, 4-chloro-2-propylphenyl,2-isopropyl-4-chlorophenyl, 4-chloro-3,5-xylyl, (2,3-, 2,4- 2,5- 2,6- or3,5-)dichlorophenyl, 4-chloro-3-fluorophenyl, (3- or4-)chloro-2-fluorophenyl, (o-, m-, or p-)trifluoro-methylphenyl, (o-,m-, or p-)ethoxyphenyl, (4- or 5-)chloro-2-methoxy-phenyl, and2,4-dichloro(5- or 6-)methylphenyl.

The compounds of the present invention will be named herein using theChemical Abstracts numbering system (see Naming and Indexing of ChemicalSubstances for Chemical Abstracts during the Ninth Collective Period(1972-1976), a reprint of section IV from the Volume 76 Index Guide.)

Compounds of this invention have been tested in one or more standardlaboratory tests which demonstrate gastric antisecretory activity. Thus,compounds of this invention have been shown to be effective asinhibitors of K⁺ -dependent ATP hydrolysis by isolated hog gastricmembranes enriched with gastric(H⁺ -K⁺)ATPase. In this system,2-[(4-methoxy-3-ethylpyridin-2-ylmethyl)sulfinyl]-benzimidazole has beenshown to be the most effective with an ID₅₀ of 3×10⁻⁶ M. In a test forin vivo inactivation of (H⁺ -K⁺)ATPase in the rat,2-[(4-ethylthio-3-methylpyridin-2-ylmethylsulfinyl]-benzimidazole wasshown to be the most effective, having an ED₅₀ of 1 mg/kg. Compounds ofthis invention have been shown to be active as inhibitors of acidsecretion in isolated gastric glands of the rabbit. In this system,2-[(4-ethylthio-3-ethylpyridin-2-ylmethyl)sulfinyl]-benzimidazole wasshown to be the most effective with an ID₅₀ of 1×10⁻⁷ M.

A significant advantage of certain of the compounds of the instantinvention, particularly those of the Formula I wherein R₁ is hydrogen, Xis ═S(O), R₃ is methyl or ethyl, R₄ is hydrogen, and R₂ is methylthio,ethylthio, or propylthio, is their long duration of activity whenadministered subcutaneously. Thus, even after 6 days2[(4-ethylthio-3-ethylpyridin-2-ylmethyl)sulfinyl]-benzimidazole and2-[(4-ethylthio-3-methylpyridin-2-ylmethyl)sulfinyl]-benzimidazoleinhibited gastric acid secretion in the rat 68 and 82%, respectively,when administered subcutaneously at a dose of 50 mg/kg.

As noted, all of the compounds of this invention are useful as gastricantisecretory agents.

Compounds of this invention are administered for gastric antisecretorypurposes orally, parenterally, (e.g., intravenously, subcutaneously,intramuscularly or intraparenterally), intradermally, rectally, orvaginally in forms such as pills, capsules, solutions, suspensions,suppositories, or bougies. The compounds of this invention areformulated into these pharmaceutical compositions by means known to thepharmaceutical art.

An ordinarily skilled physician can readily determine persons sufferingfrom gastrointestinal diseases characterized by the gastric-acid inducedeffects noted above. These conditions are treated using the compounds ofthe present invention.

Typical dose ranges for the compounds of this invention range from about0.01 μg per kg to about 250 mg per kg, preferably from about 0.1 to 100mg per kg. The choice of the use, route, and frequency of administrationof the compounds of this invention depends on the weight, age, andgastrointestinal disease of the patient and the particular compoundemployed. These decisions are readily made by a physician of ordinaryskill in the art.

However, to achieve a longer duration of action, these compounds areadministered subcutaneously. This is the preferred route foradministering the class of compounds noted above having this property,when the therapeutic objective requires it. However, when a longduration of action is not desired, and/or the compounds lack thisproperty, any convenient route of administration (e.g., oral) isemployed.

The long duration of activity of certain of the compounds of thisinvention, as noted above, allows them to be used prophylactically inthe treatment of patients with a high possibility of developing stressulcerations. Further this latter class of compounds can be administeredsubcutaneously or intramuscularly on a weekly, biweekly, or monthlybasis for the prophylaxis and/or treatment of gastric ulcer, duodenalulcer, gastritis, esophagitis, Zollinger-Ellison syndrome, stress ulcersand upper gastrointestinal bleeding. The frequency of administrationwill depend on the particular compound employed as well as the dose.

The compounds of this invention may also exert cytoprotective effects.If employed for this purpose, they could be administered as described,for example, in U.S. Pat. No. 4,359,465, particularly cols. 7 and 8thereof. The doses employed for this purpose would in general be lessthan those used for gastric antisecretory effects.

The compounds of the present invention are prepared by the methodsdepicted in Charts A-C.

In the Charts, all variables are as defined above.

In Chart A, scheme 1, a substituted α-picolyl chloride of the FormulaA-2 is reacted with a 2-mercaptobenzimidazole of the Formula A-1 in thepresence of a strong base (e.g., 10N sodium hydroxide). Substitutedα-picolyl chloride compounds are well known, readily available compoundsor may be prepared by known means, such as depicted in Chart B, asdescribed below. Similarly, the substituted 2-mercaptobenzimidazoles ofthe Formula A-1 are well known, readily available compounds or may beprepared by known means such as that depicted in Chart C as describedbelow.

The Formula A-3 product is oxidized by known means, such as treatmentwith meta-chloroperbenzoic acid, to yield the Formula A-4 product.(Sodium meta-periodate may also be used, although it is less preferred).One equivalent of sodium bicarbonate is preferably added to the reactionmixture prior to the addition of the peracid to prevent decomposition ofthe final product by the m-chlorobenzoic acid which is formed during thereaction.

In scheme 2 of Chart A, a benzimidazole compound of the formula A-5(wherein M is potassium, sodium, or lithium) is reacted with thechlorinated compound of the formula A-6 to yield the formula A-4product. The formula A-5 compounds are known and are prepared asdescribed in U.S. Pat. Nos. 4,045,563; 4,255,431; and 4,337,257; all ofwhich are incorporated herein by reference. The chlorinated compounds ofthe formula A-6 are prepared by reacting the N-oxide intermediates ofCharts B-I with known chlorinating agents (e.g., POCl₃, PCl₃, and PCl₅).

In scheme 3 of Chart A, a chlorinated benzimidazole of the formula A-7is reacted with the formula A-8 thiol to yield the formula A-3 productwhich is converted to the formula A-4 product as described above. Theformula A-7 and A-8 compounds are known or may be prepared by themethods described in U.S. Pat. Nos. 4,045,563; 4,255,431; and 4,337,257,using the intermediates prepared as described herein.

In scheme 4 of Chart A, the diamino compound of the formula A-9 isreacted with the formula A-10 acid to yield the formula A-3 productwhich is converted to the formula A-4 product as described above. Theformula A-9 and A-10 compounds are known or may be prepared as describedin U.S. Pat. Nos. 4,045,563; 4,255,431; and 4,337,257; using theintermediates prepared as described herein.

The reaction of A-1 with A-2 (Chart A, scheme 1) is carried out in amanner which is known in the art in suitable, preferably polar solvents(such as methanol, dimethylsulfoxide, acetone, dimethylformamide oracetone) with the addition or exclusion of water. It is carried out forexample in the presence of a proton acceptor. Examples of suitableproton acceptors are alkali metal hydroxides, such as sodium hydroxide,alkali metal carbonates, such as potassium carbonate, and tertiaryamines, such as pyridine, triethylamine or ethyl diisopropylamine. Thereaction temperature can be between 0° and 150° C., temperatures between50° and 100° C., and especially the boiling point of the solvent used,being preferred.

Similar reaction conditions to those for the reaction of A-1 with A-2are used in the reaction of A-7 with A-8 (Chart A, scheme 3) which iscarried out in a manner which is known in the art.

The reaction of A-9 with A-10 (Chart A, scheme 4) is preferably carriedout in polar, optionally water-containing solvents in the presence of astrong acid, for example hydrochloric acid, in particular at the boilingpoint of the solvent used.

The oxidation of sulfides A-3 is carried out in a manner which is knownper se and under conditions with which those skilled in the art arefamiliar for the oxidation of sulfides to give sulfoxides. Possibleoxidizing agents are all the reagents usually employed for oxidation ofsulfides, in particular peroxyacids, such as for example, peroxyaceticacid, trifluoroperoxyacetic acid, 3,5-dinitroperoxybenzoic acid,peroxymaleic acid or, preferably m-chloroperoxybenzoic acid. Thereaction is expediently carried out in inert solvents, for examplearomatic or chlorinated hydrocarbons, such as benzene, toluene,methylene chloride or chloroform. The reaction temperature is between-70° C. and the boiling point of the solvent used, but preferablybetween -30° C. and +20° C. (depending on the reactivity of theoxidizing agent and the degree of dilution). The oxidation with halogensor hypohalogenites (e.g., with aqueous sodium hypochloride solution),which is carried out expediently at temperatures between 0° and 30° C.has also proved to be very advantageous.

The reaction of A-5 with A-6 (Chart A, scheme 2) is preferably carriedout in inert solvents, such as those which are usually employed for thereaction of enulate ions with alkylating agents. Examples which may bementioned are aromatic solvents, such as benzene or toluene. Thereaction temperature is as a rule between 0° and 120° C. (depending onthe nature of the alkali metal atom M) preferably at the boiling pointof the solvent. For example, if M represents Li (lithium) and thereaction is carried out in benzene, the boiling point of benzene (80°C.) is preferred.

Chart B depicts a method for preparing substituted α-picolyl chloridesof the Formula A-2. A substituted 2-methyl pyridine compound of theFormula B-1 (such compounds are well-known and readily available, or maybe prepared by known means, see, e.g., R. A. Abramovitch and G. A.Poulton J. C. S., Section B, 901 (1969)) is treated with hydrogenperoxide in glacial acetic acid to yield the corresponding Formula B-2N-oxide. This compound is treated with concentrated sulfuric acid andfuming nitric acid to yield the corresponding nitro compound of theFormula B-3. The nitro compound is treated with acetyl chloride to yieldthe corresponding Formula B-4 chloride. The Formula B-4 compound isheated with a compound of the formula R₂ H in the presence of sodiumhydride and dimethylformamide or heated neat (when R₂ H is a cyclicamine) to yield the Formula B-5 compound, which is then treated withacetic anhydride to yield the Formula B-6 compound. The acyl group isremoved by mild acidic hydrolysis (e.g., treatment with 10% hydrochloricacid or saponification with base (e.g., treatment with 25% sodiummethoxide in methanol)) to yield the Formula B-7 alcohol. This alcoholis then treated with methanesulfonyl chloride and triethylamine to yieldthe corresponding substituted α-picolyl chloride of the Formula B-8.

Chart C depicts a method preparing the 2-mercaptobenzimidazoles used inChart A. A substituted phenylenediamine compound of the Formula C-1(such compounds are well known and readily available or can be preparedby known means) is treated with potassium hydroxide and carbon disulfideto yield the Formula C-2 compound. This is also described in Example 4.

All of the compounds of this invention are prepared by the proceduresdescribed above.

Certain compounds of the present invention are preferred. Thus,compounds of the Formula I, wherein R₁ is hydrogen; X is ═S(O); R₃ ismethyl or ethyl; R₄ is hydrogen, and R₂ is methylthio, ethylthio orpropylthio are preferred. More preferred are compounds wherein R₂ isethylthio. Thus,2-[(4-ethylthio-3-methylpyridin-2-ylmethyl)sulfinyl]-benzimidazole(compound 7 of Table 1) and2-[(4-ethylthio-3-ethylpyridin-2-ylmethyl)sulfinyl]-benzimidazole(compound 12 of Table 1) are preferred.2-[(4-ethylthio-3-methylpyridin-2-ylmethyl)sulfinyl]benzimidazole is themost preferred compound of this invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is seen more fully by the examples given below.

All of the compounds of the present invention are prepared using theprocedures described in the Examples below. Some physical and chemicalproperties of some of the compounds of this invention are given in Table1.

EXAMPLE 1 Procedure for the preparation of thio ethers

Refer to Chart A (conversion of A-1 to A-2 to A-3)

To a magnetically stirred 0.2-0.4M 95% ethanol solution of a Formula A-2substituted α-picolyl chloride (one equivalent) is added one equivalentof a substituted 2-mercaptobenzimidazole of Formula A-1 and twoequivalents of 10N sodium hydroxide. The contents are placed in a70°-75° C. oil bath and stirring continued for 1 hour. The reaction iscooled to room temperature, diluted with chloroform, and the chloroformis successively washed with 1N sodium hydroxide, water and saturatedbrine. The chloroform solution is dried through sodium sulfate andconcentrated in vacuo. The residual crude product is used in mostinstances in the subsequent oxidation step without further purification.When necessary, the crude product can be purified by silica gel columnchromatography and/or crystallization from common organic solvents. Thechromatography is preferably undertaken using a 1:2 mixture ofacetone:methylene chloride with a trace of triethylamine although a 2%methanol in ethyl acetate solution, or various ethyl acetate:ethermixtures are also employed. Crystallization, when necessary, ispreferably undertaken using mixtures of: ethyl acetate/ether/SkellysolveB (a commercial mixture of essentially n-hexane); ethyl acetate/diethylether; and the like.

EXAMPLE 2 Procedure for the Oxidation of Thioethers

Refer to Chart A (conversion of A-3 to A-4)

To a magnetically stirred 0.4-0.5M chloroform solution of a thioether(one equivalent), cooled in a 0°-5° C. ice-water bath, is added in a fewportions one equivalent of meta-chloroperbenzoic acid. Stirring iscontinued at 0°-5° C. for 5-10 minutes. The contents are diluted withchloroform, washed with saturated sodium bicarbonate and saturated brineand the chloroform solution is dried through sodium sulfate. Removal ofthe solvent gives the crude product which is purified by silica gelcolumn chromatography and/or crystallization as described in Example 1.

EXAMPLE 3 Preparation of Substituted α-picolyl chlorides

Refer to Chart B.

A. Conversion of B-1 to B-2.

To a magnetically stirred solution of the Formula B-1 2-methyl pyridine(approximately 0.40 mmol) in 230 ml of acetic acid is added 38 ml of 30%hydrogen peroxide. The contents are placed in an oil bath maintained at70°-80° C. After 2.5 hours, an additional 23 ml of hydrogen peroxide isadded and heating continued for an additional 6 hours. The reactionflask is then cooled in an ice-acetone bath and 327 ml of a 45%potassium hydroxide solution is slowly added. The aqueous solution isthoroughly extracted with chloroform, dried over sodium sulfate, and themethylene chloride is removed in vacuo. The residual solid is dried invacuo at 50° C. to afford the Formula B-2 product which is used withoutfurther purification.

B. Conversion of B-2 to B-3.

The Formula B-2 N-oxide (approximately 0.50 mmol) is melted in a 60° C.oil bath. To this melt is slowly and cautiously added 146 ml ofconcentrated sulfuric acid with ice-bath-cooling. The solution is cooledin an ice-bath and 76 ml of fuming nitric acid (90%) is added dropwiseover a 10 minute period. The cooling bath is removed when the solutiontemperature remains constant (22° C.). The contents are then placed inan oil bath initially at 30° C. and the temperature is graduallyincreased to 95° C. over a period of 2 hours. Heating is continued at95° C. for 2 hours, the reaction is cooled to 10° C. in a cooling bath,poured into 1 liter of crushed ice and neutralized to pH 3 with 650 mlof 10N sodium hydroxide. The solid that appears is filtered, washed with500 ml of water, dried at 50° C. in vacuo and recrystallized from ethylacetate-ether to give the Formula B-3 product. The filtrate is extractedwith chloroform and dried over sodium sulfate.

C. Conversion of B-3 to B-4.

To a magnetically stirred solution of 25 ml of acetyl chloride is addedapproximately 27.50 mmol of Formula B-3 compound as a solid in severalportions. After addition, the contents are heated in a 100° C. oil bathfor 10 minutes. The solution is cooled to 25° C., poured into 200 ml ofcrushed ice and treated with 48 g of solid potassium carbonate to pH 9.The aqueous solution is extracted with chloroform, dried over sodiumsulfate and concentrated in vacuo to give the crude product which ischromatographed on 160 g of silica gel and eluted with methylenechloride-acetone (2:1).

D. Conversion of B-4 to B-5.

To a magnetically stirred suspension of sodium hydride (60% oildispersion, 0.702 g., 17.54 mmol) in 20 ml of DMF is added approximately17.54 mmol), of the R₂ H compound. Stirring is continued at 25° C. for0.5 hours. At the end of this period, approximately 11.70 mmol of theB-4 compound in dimethylformamide (DMF) is added and this reaction isheated in a 100° C. oil bath for 1 hour. The contents are poured into 75ml of ice water, extracted thoroughly with chloroform, the chloroformextracts are washed with saturated brine, and the mixture is dried oversodium sulfate and concentrated in vacuo. The crude product ischromatographed on 175 g of silica gel and eluted withchloroform:methanol (95:5).

E. Conversion of B-5 to B-6.

Approximately 15.82 mmol of the B-5 compound are treated with 9 ml ofacetic anhydride and heated in a 100° C. oil bath for 15 minutes. Thecontents are cooled to 25° C. and treated with 75 ml of saturated sodiumcarbonate solution and then with solid sodium carbonate and extractedthoroughly with chloroform or ethyl acetate. The organic phase is washedwith sodium carbonate solution, saturated brine, dried over sodiumsulfate and concentrated in vacuo to afford the B-6 compound which isused without further purification.

F. Conversion of B-6 to B-7.

Approximately 13.21 mmol of the B-6 compound in 28 ml of 10%hydrochloric acid are heated in an 100° C. oil bath for 0.5 hours. Thereaction is worked up in the same manner as described in Part E. Thecrude product is chromatographed on 150 g of silica gel and eluted withmethylene chloride-acetate (4:1) to afford the Formula B-7 product.

G. Conversion of B-7 to B-8.

To approximately 2.50 mmol of the B-7 compound in 10 ml of methylenechloride are added 202 μl (2.63 mmol) of methanesulfonyl chloride and381 μl (2.75 mmol) of triethylamine. Stirring is continued at 25° C. for48 hours. The solution is then diluted with methylene chloride, washedwith water and then saturated brine, dried over sodium sulfate andconcentrated in vacuo to give the B-8 product which is used withoutfurther purification.

EXAMPLE 4 Preparation of Substituted 2-mercaptobenzimidazoles

Refer to Chart C (conversion of C-1 to C-2).

To a magnetically stirred solution of the Formula C-1 diamine, as thehydrochloride (0.115 mol) in 400 ml of ethanol-water (4:1) is added 2molar equivalents of 85% potassium hydroxide solution and 20 ml ofcarbon disulfide. The contents are warmed in a 75°-80° C. oil bath for2.5 hours and the solvent is removed in vacuo. To the residual thickslurry is added 200 ml of water, the contents heated to boiling, and 95%ethanol is added until a transparent solution is obtained. The solutionis filtered, the filtrate is allowed to stand at 25° C. and theresulting crystalline solid is collected, and washed with water-ethanol.Drying n vacuo affords the desired product.

                                      TABLE I                                     __________________________________________________________________________                                                    Melting                                                                 Mass  Point Yield                   #  Compound Name R.sub.1                                                                            X   R.sub.3                                                                            R.sub.2                                                                              R.sub.4                                                                           Spectra.sup.1                                                                       (°C.)                                                                        (%) Color               __________________________________________________________________________    1  2-[(4-methylthio-                                                                           CH.sub.3 O--                                                                       ═S(O)                                                                         C.sub.2 H.sub.5 --                                                                 --SCH.sub.3                                                                          H-- 400.0556 C                                                                          141-142                                                                             63  pale                   3-ethylpyridin-2-                      400.0559 F      green                  ylmethyl)sulfinyl]-                    [M + K].sup.+                          5-methoxybenzimidazole                                                     2  2-[(4-methylthio-3-                                                                         H--  ═S(O)                                                                         C.sub.2 H.sub.5 --                                                                 --SCH.sub.3                                                                          H-- 370.0450 C                                                                          154   53  pale                   ethylpyridin-2-yl-                     370.0470 F      green                  methyl)sulfinyl]-                      [M + K].sup.+                          benzimidazole                                                              3  2-[(4-methylthio-3-                                                                         F.sub.3 C--                                                                        ═S(O)                                                                         C.sub.2 H.sub.5 --                                                                 --SCH.sub.3                                                                          H-- 438.0324 C                                                                          145- 147                                                                            50  gray                   ethylpyridin-2-yl-                     438.0339 F                             methyl)sulfinyl]-5-                    [M + K].sup.+                          trifluoromethylbenz-                                                          imidazole                                                                  4  2-[(4-morpholinyl-                                                                          H--  ═S(O)                                                                         C.sub.2 H.sub.5                                                                    morpholinyl                                                                          H-- 371.1542 C                                                                          146-147   off                    3-ethylpyridin-2-                      371.1554 F      white                  ylmethyl)sulfinyl]-                    [M + H].sup.+                          benzimidazole                                                              5  2-[(4-ethylthio-3-                                                                          F.sub.3 C--                                                                        ═S(O)                                                                         C.sub.2 H.sub.5 --                                                                 --SC.sub.2 H.sub.5                                                                   H-- 452.0480 C                                                                          139-141                                                                             50                         ethylpyridin-2-yl-                     452.0500 F                             methyl)sulfinyl]-5-                    [M + K].sup.30                                                                      trifluoromethylbenz-             imidazole                                                                  6  2-[(4-ethylthio-3-                                                                          CH.sub.3 O--                                                                       ═S(O)                                                                         CH.sub.3 --                                                                        --SC.sub.2 H.sub.5                                                                   H-- 400.0556 C  76  tan                    methylpyridin-2-                       400.0563 F                             ylmethyl)sulfinyl]-                    [M + K].sup.+                          5-methoxybenzimida-                                                           zole                                                                       7  2-[(4-ethylthio-3-                                                                          H--  ═ S(O)                                                                        CH.sub.3 --                                                                        --SC.sub.2 H.sub.5                                                                   H-- 370.0450 C                                                                          148-151                                                                             58  white                  methylpyridin-2-yl                     370.0455 F                             methyl)sulfinyl]-                      [M + K].sup.+                          benzimidazole                                                              8  2-[(4-benzyloxy-3-                                                                          H--  ═S(O)                                                                         C.sub.2 H.sub.5 --                                                                 benzyloxy                                                                            H-- 460.1097 C                                                                          145-147   white                  ethylpyridin-2-yl-                     460.1091 F                             methyl)sulfinyl]-                      [M + K].sup.+                          benzimidazole                                                              9  2-[(4-benzyloxy-3-                                                                          CH.sub.3 O--                                                                       ═S(O)                                                                         C.sub.2 H.sub.5 --                                                                 benzyloxy                                                                            H-- 460.1097 C                                                                          148-152                                                                             77  pale                   ethylpyridin-2-yl-                     460.1091 F      yellow                 methyl)sulfinyl]-5-                    [M + K].sup.+                          methoxybenzimidazole                                                       10 2-[(4-benzoyloxy-3-                                                                         H--  ═S                                                                            C.sub.2 H.sub.5 --                                                                 benzyloxy                                                                            H-- 376.1483 C  74  white                  ethylpyridin-2-yl-                     376.1476 F                             methyl)thio]benz-                      [M + H].sup.+                          imidazole                                                                  11 2-[ (4-benzyloxy-3-                                                                         CH.sub.3 O--                                                                       ═S                                                                            C.sub.2 H.sub.5 --                                                                 benzyloxy                                                                            H-- 406.1489 C  75  white                  ethylpyridin-2-yl-                     406.1580                               methyl)thio]-5-                        [M.sup.+ ]                             methoxybenzimidazole                                                       12 2-[(4-ethylthio-3-                                                                          H--  ═S(O)                                                                         C.sub.2 H.sub.5 --                                                                 --SC.sub.2 H.sub.5 --                                                                H-- 384.0607 C                                                                          153-154                                                                             57  white                  ethylpyridin-2-yl-                     384.0591 F                             methyl)sulfinyl]-                      [M +K].sup.+                           benzimidazole                                                              13 2-[(4-ethylthio-3-                                                                          CH.sub.3 O--                                                                       ═S(O)                                                                         C.sub.2 H.sub.5 --                                                                 --SC.sub.2 H.sub.5                                                                   H-- 452.0271 C                                                                          111-114                                                                             83  off                    ethylpyridin-2-yl-                     452.0257 F      white                  methyl)sulfinyl]-5-                    [M +                                   methoxybenzimidazole                   2K - H].sup.+                       14 2-[(4-methoxy-3-                                                                            H--  ═S                                                                            C.sub.2 H.sub.5 --                                                                 --OCH.sub.3                                                                          H-- 338.0729 C  80  white                  ethylpyridin-2-yl-                     338.0732 F                             methyl)thio]-benz-                     [M + K].sup.+                          imidazole                                                                  15 2-[(4-methoxy-3-                                                                            H--  ═S(O)                                                                         C.sub.2 H.sub.5 --                                                                 --OCH.sub.3                                                                          H-- 354.0679 C                                                                          136-137.5                                                                           85  tan                    ethylpyridin-2-yl-                     354.0685 F                             methyl)sulfinyl]-                      [M + K].sup.+                          benzimidazole                                                              16 2-[(4-methoxy-3-                                                                            CH.sub.3 O--                                                                       ═S(O)                                                                         C.sub.2 H.sub.5 --                                                                 --OCH.sub.3                                                                          H-- 384.0784 C                                                                          83-87 93  pale                   ethylpyridin-2-yl-                     384.0776 F      white                  methyl)sulfinyl]-                      [M + K].sup.+                          5-methoxybenzimidazole                                                     17 2-[(4-methoxy-3-                                                                            CH.sub.3 O--                                                                       ═S                                                                            C.sub.2 H.sub.5 --                                                                 --OCH.sub.3                                                                          H-- 368.0835 C  79  white                  ethylpyridin-2-yl-                     368.0845 F                             methyl)thio]-5-                        [M + K].sup.+                          methoxybenzimidazole                                                       18 2-[(4-benzloxypy-                                                                           CH.sub.3 O--                                                                       ═S(O)                                                                         H--  benzyloxy                                                                            H-- 393.1147 C                                                                          74-44 74  white                  ridin-2-ylmethyl)-                     393.1156 F                             sulfinyl]-5-methoxy-                   [M.sup.+ ]                             benzimidazole                                                              19 2-[(4-piperidinyl-                                                                          CH.sub.3 O--                                                                       ═S(O)                                                                         H--  piperidinyl                                                                          C.sub.2 H.sub.5 --                                                                398.1176 C                                                                          99-100                                                                              63                         5-ethylpyridin-2-yl-                   398.1767 F                             methyl)sulfinyl]-5-                    [M.sup.+ ]                             methoxybenzimidazole                                                       20 2-[(4-morpholinyl-5-                                                                        CH.sub.3 O--                                                                       ═S(O)                                                                         H--  morpholinyl                                                                          C.sub.2 H.sub.5 --                                                                400.1569 C                                                                          100-102                                                                             71                         ethylpyridin-2-yl-                     400.1566 F                             methyl)-sulfinyl]-5-                   [M.sup.+ ]                             methoxybenzimidazole                                                       21 2-[(4-N,N--dimethyl-                                                                        CH.sub.3 O--                                                                       ═S(O)                                                                         H--  --N(CH.sub.3).sub.2                                                                  --C.sub.2 H.sub.5                                                                 451.0608 C                                                                          138   50  rust                   amino-5-ethylpyridin-                  451.0604 F                             2-ylmethyl)sulfinyl]-                  [M.sup.+ ]                             5-methoxybenzimidazole                                                     22 2-[(4-phenylthio-3,5-                                                                       CH.sub.3 O--                                                                       ═S(O)                                                                         CH.sub.3 --                                                                        phenylthio                                                                           CH.sub.3 --                                                                       423.1075 C  81  white                  dimethylpyridin-2-yl-                  423.1098 F                             methyl)sulfinyl]-5-                    [M.sup.+ ]                             methoxybenzimidazole                                                       23 2-[(4-phenylthio-3,5-                                                                       CH.sub.3 O--                                                                       ═S                                                                            CH.sub.3                                                                           phenylthio                                                                           CH.sub.3 --                                                                       407.1126 C  72  white                  dimethylpyridin-2-yl-                  407.1132 F                             methyl)thio]-5-methoxy-                [M.sup.+ ]                             benzimidazole                                                              24 2-[(4-ethylthio-3,5-                                                                        CH.sub.3 O--                                                                       ═S(O)                                                                         CH.sub.3 --                                                                        --SC.sub.2 H.sub.5                                                                   CH.sub.3 --                                                                       375.1075 C                                                                          137-138                                                                             67  white                  dimethylpyridin-2-yl-                  375.1079 F                             methyl)sulfinyl]-5-                    [M.sup.+ ]                             methoxybenzimidazole                                                       25 2-[(4-ethylthio-3,5-                                                                        CH.sub.3 O--                                                                       ═S                                                                            CH.sub.3 --                                                                        --SC.sub.2 H.sub.5                                                                   CH.sub.3 --                                                                       359.1126 C  70  golden                 dimethylpyridin-2-yl-                  359.1137 F                             methyl)thio]-5-methoxy-                [M.sup.+ ]                             benzimidazole                                                              26 2-[(4-phenylthio-5-                                                                         CH.sub.3 O--                                                                       ═S(O)                                                                         H--  phenylthio                                                                           --C.sub.2 H.sub.5                                                                 423.1075 C  88  white                  ethylpyridin-2-yl-                     423.1111 F                             methyl)sulfinyl]-5-                    [M.sup.+ ]                             methoxybenzimidazole                                                       27 2-[(4-phenylthio-5-                                                                         CH.sub.3 O--                                                                       ═S                                                                            H--  phenylthio                                                                           --C.sub.2 H.sub.5                                                                 407.1126 C  68  white                  ethylpyridin-2-yl-                     407.1140 F                             methyl)thio]-5-methoxy-                [M.sup.+ ]                             benzimidazole                                                              28 2-[(4-phenylthio-                                                                           CH.sub.3 O--                                                                       ═S(O)                                                                         H--  phenylthio                                                                           --H 395.0762 C  76  white                  pyridin-2-ylmethyl)-                   395.0789 F                             sulfinyl]-5-methoxy-                   [M.sup.+ ]                             benzimidazole                                                              29 2-[(4-phenylthio-                                                                           CH.sub.3 O--                                                                       ═S                                                                            H--  phenylthio                                                                           --H 379.0813 C  77  white                  pyridin-2-ylmethyl)-                   379.0803 F                             thio]-5-methoxybenz-                   [M.sup.+ ]                             imidazole                                                                  30 2-[(4-ethylthio-5-                                                                          CH.sub.3 O--                                                                       ═S(O)                                                                         H--  --SC.sub.2 H.sub.5                                                                   --C.sub.2 H.sub.5                                                                 375.1075 C                                                                          97-101                                                                              68  white                  ethylpyridin-2-yl-                     375.1057 F                             methyl)sulfinyl]-5-                    [M.sup.+ ]                             methoxybenzimidazole                                                       31 2-[(4-ethylthio-5-                                                                          CH.sub.3 O--                                                                       ═S                                                                            H--  --SC.sub.2 H.sub.5                                                                   --C.sub.2 H.sub.5                                                                 359.1126 C                                                                          124-125                                                                             74  cream                  ethylpyridin-2-yl-                     359.1134 F                             methyl)thio-5-methoxy-                 [M.sup.+ ]                             benzimoidazole                                                             32 2-[(4-ethylthio-                                                                            CH.sub.3 O--                                                                       ═S(O)                                                                         H--  --SC.sub.2 H.sub.5                                                                   H-- 347.0762 C                                                                          154-155                                                                             57  white                  pyridin-2-ylmethyl)-                   347.0779 F                             sulfinyl]-5-methoxy-                   [M.sup.+ ]                             benzimidazole                                                              33 2-[(4-ethylthio-                                                                            CH.sub.3 O--                                                                       ═S                                                                            H--  --SC.sub.2 H.sub.5                                                                   H-- 331.0813 C                                                                          130-132                                                                             65  white                  pyridin-2-ylmethyl)-                   331.0812                               thio]-5-methoxybenz-                   [M.sup.+ ]                             imidazole                                                                  34 2-[(4-phenoxy-5-                                                                            CH.sub.3 O--                                                                       ═S(O)                                                                         H--  phenoxy                                                                              C.sub.2 H.sub.5 --                                                                407.1304 C  67  pink                   ethylpyridin-2-yl-                     407.1318 F                             methyl)sulfinyl]-                      [M.sup.+ ]                             5-methoxybenzimidazole                                                     35 2-[(4-phenoxypyridin-                                                                       CH.sub.3 O--                                                                       ═S(O)                                                                         H--  phenoxy                                                                              H-- 379.0991 C  68  purple                 2-ylmethyl)sulfinyl]-                  379.0988 F                             5-methoxybenzimidazole                 [M.sup.+ ]                          36 2-[(4-phenoxy-5-ethyl-                                                                      CH.sub.3 O--                                                                       ═S                                                                            H--  phenoxy                                                                              --C.sub.2 H.sub.5                                                                 391.1354 C  62  white                  pyridin-2-ylmethyl)-                   391.1358 F                             thio]-5-methoxybenz-                   [M.sup.+ ]                             imidazole                                                                  37 2-[(4-phenoxy-pyridin-                                                                      CH.sub.3 O--                                                                       ═S                                                                            H--  phenoxy                                                                              H-- 363.1041 C  66  colorless              2-ylmethyl)thio]-5-                    363.1053 F                             methoxybenzimidazole                   [M.sup.+ ]                          38 2-[(4-(2,6-dimethyl-                                                                        CH.sub.3 O--                                                                       ═S                                                                            H--  dimethyl-                                                                            H-- 391.1354 C  55  white                  phenoxy)-2-pyridinyl)-      phenoxy    391.1366 F                             methylthio-5-methoxy-                  [M.sup.+ ]                             benzimidazole                                                              39 2-[(4-(2,6-dimethyl-                                                                        CH.sub.3 O--                                                                       ═S(O)                                                                         H--  dimethyl-                                                                            H-- 407.1304 C  82  pink                   phenoxy)-2-pyridinyl)-      phenoxy    407.1318 F                             methylsulfinyl]-5-                     [M.sup.+ ]                             methoxybenzimidazole                                                       40 5-methoxy-2-[[[4-                                                                           CH.sub.3 O--                                                                       ═S                                                                            H--  benzyloxy                                                                            H-- 377.1197 C                                                                          149-151                                                                             75  white                  (phenoxymethoxy)-                      377.1198 F                             2-pyridinyl]methyl]-                   [M.sup.+ ]                             thio]-1H--benzimido-                                                          zole                                                                       41 5-methoxy-2-[[[4-                                                                           CH.sub.3 O--                                                                       ═S                                                                            H--  trimethoxy-                                                                          H-- 467.1515 C                                                                          66-70 80  white                  [(3,4,5-trimethoxy-         benzyloxy  467.1485                               phenyl)methoxy]-2-                     [M.sup.+ ]                             pyridinyl]methyl]-                                                            thio]-1H--benzimido-                                                          zole                                                                       42 5-methoxy-2-[[[4-                                                                           CH.sub.3 O--                                                                       ═S(O)                                                                         H--  trimethoxy-                                                                          H-- 522.1085 C                                                                          70-72 88  white                  [(3,4,5-trimethoxy-         benzyloxy  522.1101 F                             phenyl)methoxy]-2-                     [M + K].sup.+                          pyridinyl]methyl]-                                                            sulfinyl]-1H--benz-                                                           imidazole                                                                  43 2-[[[3-ethyl-4-                                                                             H--  ═S(O)                                                                         C.sub.2 H.sub.5 --                                                                 benzylthio                                                                           H-- 408.1204 C                                                                          141-143                                                                             68  white                  [phenylmethyl)-                        408.1226 F                             thiol-2-pyridinyl]-                    [M + H].sup.+                          methyl[sulfinyl]-                                                             1H--benzimidazole                                                          44 2-[[[3-ethyl-4-                                                                             CH.sub.3 O--                                                                       ═S(O)                                                                         C.sub.2 H.sub.5                                                                    benzylthio                                                                           H-- 476.0869 C                                                                          69-74 75  gray                   [(phenylmethyl)-                       476.0888 F                             thiol-2-pyridinyl]-                    [M + K].sup.+                          methyl]sulfinyl-5-                                                            methoxy-1H--benzimida-                                                     zole                                                                          45 2-[[[4-(butylthio)-                                                                         H--  --S(O)                                                                            C.sub.2 H.sub.5                                                                    butylthio                                                                            H-- 374.1361 C                                                                          125-127                                                                             60  white                  3-ethyl-2-pyridinyl]-                  374.1389 F                             methyl]sulfinyl]-1H--                  [M + H].sup.+                          benzimidazole                                                              46 2-[[[4-(butylthio)-                                                                         CH.sub.3 O--                                                                       --S(O)                                                                            C.sub.2 H.sub.5 --                                                                 butylthio                                                                            H-- 404.1466 C                                                                          92-96 58  pale                   3-ethyl-2-pyridinyl]-                  404.1488 F      green                  methyl]sulfinyl]-5-                    [M + H].sup.+                          methoxy-1H--benzimidzole                                                   47 2-[[[2-ethyl-4-                                                                             H--  ═S(O)                                                                         C.sub.2 H.sub.5                                                                    propylthio                                                                           H-- 398.0763 C                                                                          132-133                                                                             61  white                  (propylthio)-2-                        398.0782 F                             pyridinyl]methyl]-                     [M + K].sup.+                          sulfinyl]-1H--benz-                                                           imidazole                                                                  48 2-[[[3-ethyl-4-                                                                             CH.sub.3 O--                                                                       ═S(O)                                                                         C.sub.2 H.sub.5 -                                                                  propylthio                                                                           H-- 428.0869 C                                                                          130-133                                                                             62  white                  (propylthio)-2-                        428.0857 F                             pyridinyl]methyl]-                     [M + K].sup.+                          sulfinyl-5-methoxy-                                                           1H--benzimidazole                                                          49 2-[[[3-methyl-4-                                                                            H--  ═S(O)                                                                         CH.sub.3                                                                           methylthio                                                                           H-- 356.0294 C                                                                          166.0-166.5                                                                         61  white                  (methylthio)-2-                        356.0313 F                             pyridinyl]methyl]-                     [M + K].sup.+                          sulfinyl]-1H--benz-                                                           imidazole                                                                  50 2-[[[3-methyl-4-                                                                            H--  ═S(O)                                                                         CH.sub.3 --                                                                        isopropyl-                                                                           H-- 346.1048 C                                                                          153-154                                                                             69  tan                    [(1-methylethyl)-           thio       346.1048 F                             thio-2-pyridinyl]-                     [M + K].sup.+                          methyl]sulfinyl]-                                                             1H--benzimidazole                                                          51 2-[[[4-[(1,1-di-                                                                            H--  ═S(O)                                                                         CH.sub.3 --                                                                        t-butylthio                                                                          H-- 398.0763 C                                                                          115-118                                                                             50  blue                   methylethyl)thio]-                     398.0775 F                             3-methyl-2-pyridinyl]-                 [M + K].sup.+                          methyl]sulfinyl]-                                                             1H--benzimidazole                                                          52 2-[[[4-(ethylthio)-                                                                         H--  ═S                                                                            CH.sub.3 --                                                                        ethylthio                                                                            H-- 316.0942 C                                                                          158-159                                                                             62  white                  3-methyl-2-pyridinyl]-                 316.0931 F                             methyl]thiol-1H--benz-                 [M + H].sup.+                          imidazole                                                                  53 2-[[[3-methyl-4-                                                                            H--  ═S(O)                                                                         CH.sub.3 --                                                                        propenyl-                                                                            H-- 344.0891 C                                                                          150-151                                                                             69  white                  (2-propenylthio)-2-         thio       344.0906 F                             pyridinyl]methyl]-                     [M + H].sup.+                          sulfinyl]-1H--benz-                                                           imidazole                                                                  54 2-[[[3-n-propyl-                                                                            H    ═S(O)                                                                         n-propyl                                                                           ethylthio                                                                            H-- 398.0763 C                                                                          118-120                                                                             60  purple                 4-(ethylthio)-2-                       398.0749 F                             pyridinyl]methyl-                      [M + K].sup.+                          sulfinyl-1H--benz-                                                            imidazole                                                                  55 2-[[[3-n-propyl-                                                                            H    ═S(O)                                                                         n-propyl                                                                           methylthio                                                                           H-- 384.0607 C                                                                          110-112                                                                             63  gray                   4-(methylthio)-2-                      384.0591 F                             pyridinyl]methyl-                      [M + K].sup.+                          sulfinyl-1H--benz-                                                            midazole                                                                   56 2-[[(4-cyclohexyl-                                                                          H    ═S(O)                                                                         CH.sub.3                                                                           4-cyclo-                                                                             H-- 424.092 C                                                                           142-144                                                                             44  tan                    thio]-3-methyl-2-py-        hexylthio  424.095 F                              ridinyl]methyl]sul-                                                           finyl]-1H--benzimidazole                                                   __________________________________________________________________________     .sup.1 Mass spectral analysis calculated using fastatom bombardment (FAB)     "C" means calculated result, "F" indicates result found.                      The bracketed material indicates the ion fragment measured.                   ##STR1##

I claim:
 1. A compound of the formula I:wherein X is(a) ═S, or (b) ═SO;wherein R₁ is(a) hydrogen, (b) methyl, (c) methoxy, or (d)trifluoromethyl; wherein R₂ is(a) --SR₅, wherein R₅ is(a) (C₁ -C₄)alkyl,(b) (C₁ -C₄)alkenyl, (c) PhX, (d) --CH₂ PhX, or (e) (C₃ -C₁₀)cycloalkyl;wherein (PhX) is phenyl substituted by zero to 3 of the following:(a)(C₁ -C₄)alkyl, (b) chloro, (c) fluoro, (d) bromo, (e) nitro, (f)trifluoromethyl; or (g) OR₃ ; wherein R₃ and R₄ are the same ordifferent and are(a) hydrogen, or (b) (C₁ -C₄)alkyl.
 2. A compound ofclaim 1, wherein R₁ is hydrogen; X is ═S(O); R₃ is methyl or ethyl; R₄is hydrogen; and R₂ is methylthio, ethylthio, or propylthio.
 3. Acompound of claim 2, wherein R₂ is ethylthio.
 4. A compound of claim 1,selected from the group consistingof:2-[(4-methylthio-3-ethylpyridin-2-ylmethyl)sulfinyl]-5-methoxy-benzimidazole,2-[(4-methylthio-3-ethylpyridin-2-ylmethyl)sulfinyl]-benzimidazole,2-[(4-ethylthio-3-ethylpyridin-2-ylmethyl)sulfinyl]-5-trifluoromethylbenzimidazole,2-[(4-ethylthio-3-methylpyridin-2-ylmethyl)sulfinyl]-benzimidazole,2-[(4-ethylthio-3-ethylpyridin-2-ylmethyl)sulfinyl]-5-methoxybenzimidazole,2-[(4-phenylthio-3,5-dimethylpyridin-2-ylmethyl)sulfinyl]-5-methoxybenzimidazole,2-[(4-phenylthio-3,5-dimethylpyridin-2-ylmethyl)thio]-5-methoxybenzimidazole,2-[(4-ethylthio-3-dimethylpyridin-2-ylmethyl)sulfinyl]-5-methoxybenzimidazole,2-[(4-ethylthio-3,5-dimethylpyridin-2-ylmethyl)thio]-5-methoxybenzimidazole2-[(4-phenylthio-5-ethylpyridin-2-ylmethyl)sulfinyl]-5-methoxybenzimidazole2-[(4-phenylthio-5-ethylpyridin-2-ylmethyl)thio]-5-methoxybenzimidazole,2-[(4-phenylthiopyridin-2-ylmethyl)sulfinyl]-5-methoxybenzimidazole,2-[(4-phenylthiopyridin-2-ylmethyl)thio]-5-methoxybenzimidazole,2-[(4-ethylthio-5-ethylpyridin-2-ylmethyl)sulfinyl]-5-methoxybenzimidazole,2-[(4-ethylthio-5-ethylpyridin-2-ylmethyl)thio]-5-methoxybenzimidazole,2-[(4-ethylthiopyridin-2-ylmethyl)sulfinyl]-5-methoxybenzimidazole,2-[[3-ethyl-4-[(phenylmethyl)thiol-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole,2-[[3-ethyl-4-[(phenylmethyl)thiol-2-pyridinyl]methyl]sulfinyl]-5-methoxy-1H-benzimidazole,2-[[[4-(butylthio)-3-ethyl-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole,2-[[[4-(butylthio)-3-ethyl-2-pyridinyl]methyl]sulfinyl]-5-methoxy-1H-benzimidazle,2-[[3-ethyl-4-(propylthio)-2-pyridinyl]methyl]sulfinyl]-5-methoxy-1H-benzimidazole,2-[[3-methyl-4-[(1-methylethyl)thio-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole,2-[[[4-[(1,1-dimethylethyl)thio]-3-methyl-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole,2-[[[3-methyl-4-(2-propenylthio)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole,2-[[[3-n-propyl-4-(ethylthio)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole2-[[[3-n-propyl-4-(methylthio)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole,and2-[[[(4-cyclohexylthio]-3-methyl-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole.5.2-[(4-Methylthio-3-ethylpyridin-2-ylmethyl)sulfinyl]-5-trifluoromethylbenzimidazole;2-[[[4-(butylthio)-3-ethyl-2-pyridinyl]methyl]sulfinyl]-5-methoxy-b1H-benzimidazole; and2-[[[3-methyl-4-(methylthio)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole,compounds of claim
 2. 6.2-[(4-Ethylthio-3-methylpyridin-2-ylmethyl)sulfinyl]-benzimidazole and2-[[[4-(ethylthio)-3-methyl-2-pyridinyl]methyl-2-pyridinyl]methyl]thiol-1H-benzimidazole,compounds of claim
 3. 7.2-[(4-Ethylthio-3-methylpyridin-2-ylmethyl)sulfinyl]-benzimidazole, acompound of claim 13.